Successful primary prevention of chronic kidney disease (CKD) relies on understanding the pathways leading to established disease, including how they extend over the life-course. Projects in this thesis examine risk factors for CKD and consequences of impaired kidney function from a life-course perspective using routinely collected health-data in Swedish registers and research cohort data from the United Kingdom.

The main findings regarding risk factors for CKD are, that markers of health and development determined at conscription assessment in adolescence, independently predict diagnosis of end-stage renal disease in middle age. We also identified a persistent increased risk of CKD following hospital admission with pneumonia in adulthood with highest magnitude risks in years immediately following infection, but still statistically significantly raised more than 15 years after the pneumonia episode. Our main findings relevant to predicting the consequences of impaired kidney function are that creatinine and cystatin C used clinically to estimate kidney function (estimated glomerular filtration rate, eGFR) have associations with increased mortality risk independent of GFR measured with an exogenous filtration marker (mGFR). If cystatin C and creatinine are combined, adding mGFR does not improve mortality risk prediction. Another important finding is that moderately reduced eGFR is only associated with a statistically significant increased mortality risk among individuals in the lowest third of the distribution of grip strength in a general population sample followed for 4-5 years, after adjustment for potential confounding factors.

These results highlight the importance of adopting a life-course perspective when studying risk factors for CKD, since these associations can extend over different stages in the life-course. When assessing increased mortality risk associated with measures of GFR, combining cystatin and creatinine improves risk prediction. Potential effect modification across subgroups, including by grip strength, should be considered.

Abstract [en]

Background: Identification of predictors of end-stage renal disease (ESRD) in adolescence could provide intervention targets and improve understanding of the cause.

Study Design: Register-based nested case-control study.

Setting & Participants: A cohort of all Swedish male residents born from 1952 through 1956 who attended mandatory military conscription examinations in late adolescence was used to identify 534 cases and 5,127 controls matched by birth year, county, and vital status.

Measurements: Physical working capacity and cognitive function score in late adolescence. Head of household's occupation and household crowding measured as person-per-room ratio from the 1960 census when participants were children.

Results: Proteinuria is associated notably with future ESRD, with an adjusted OR of 7.72 (95% CI, 3.94-15.14; P < 0.001) for trace or positive dipstick findings. ESR has a dose-dependent association with ESRD with an adjusted OR of 2.07 (95% CI, 1.14-3.75; P = 0.02) for ESR > 15 mm/h. Hypertension is associated strongly with future ESRD with an OR of 3.97 (95% CI, 2.08-7.59; P < 0.001) for grade 2 hypertension and higher. Elevated BMI is associated statistically significantly with increased ESRD risk with an OR of 3.53 (95% CI, 2.04-6.11; P < 0.001) for BMI >= 30 compared with 18.5-<25kg/m(2).

Limitations: The study was limited to men, with no initial estimation of glomerular filtration rate, and information on smoking was unavailable.

Conclusions: ESR, proteinuria, BMI, and blood pressure in late adolescence are independent predictors of ESRD in middle-aged men. This highlights the long natural history and importance of adopting a life-course approach when considering the cause of chronic kidney disease. (C) 2014 by the National Kidney Foundation, Inc.

Abstract [en]

Background: Cystatin C may add explanatory power for associations with mortality in combination with other filtration markers, possibly indicating pathways other than glomerular filtration rate (GFR). However, this has not been firmly established since interpretation of associations independent of measured GFR (mGFR) is limited by potential multicollinearity between markers of GFR. The primary aim of this study was to assess associations between cystatin C and mortality, independent of mGFR. A secondary aim was to evaluate the utility of combining cystatin C and creatinine to predict mortality risk.

Methods: Cox regression was used to assess the associations of cystatin C and creatinine with mortality in 1157 individuals referred for assessment of plasma clearance of iohexol.

Results: Since cystatin C and creatinine are inversely related to mGFR, cystatin C - 1 and creatinine - 1 were used. After adjustment for mGFR, lower cystatin C - 1 (higher cystatin C concentration) and higher creatinine - 1 (lower creatinine concentration) were independently associated with increased mortality. When nested models were compared, avoiding the potential influence of multicollinearity, the independence of the associations was supported. Among models combining the markers of GFR, adjusted for demographic factors and comorbidity, cystatin C - 1 and creatinine - 1 combined explained the largest proportion of variance in associations with mortality risk ( R 2 = 0.61). Addition of mGFR did not improve the model.

Conclusions: Our results suggest that both creatinine and cystatin C have independent associations with mortality not explained entirely by mGFR and that mGFR does not offer a more precise mortality risk assessment than these endogenous filtration markers combined.

Abstract [en]

Background: Although acute onset kidney complications associated with severe infections including pneumonia are well characterized, little is known about possible subsequent delayed risk of chronic kidney disease (CKD).

Patients and methods: Associations between hospital admission with pneumonia in adulthood and raised risks of subsequent CKD were evaluated in a cohort of all male residents in Sweden born from 1952 to 1956 (n=284,198) who attended mandatory military conscription examinations in late adolescence (n=264,951) and were followed up through 2009. CKD and pneumonia were identified using Swedish national registers, and their associations were evaluated using Cox regression. Excluding the first year, the subsequent period was divided into <= 5, > 5-<= 15, and > 15 years after hospital admission with pneumonia. Follow-up ended on the date of first incident diagnosis of kidney disease, death, emigration, or December 31, 2009, whichever occurred first.

Results: During a median follow-up of 36.7 (interquartile range 35.3-37.9) years from late adolescence, 5,822 men had an inpatient pneumonia diagnosis without contemporaneous kidney disease. Among exposed men, 136 (2.3%) were later diagnosed with CKD compared with 2,749 (1.2%) of the unexposed. The adjusted hazard ratio for CKD in the first year after the first episode of pneumonia was 14.55 (95% confidence interval, 10.41-20.32), identifying early onset kidney complications and possibly pre-existing undiagnosed CKD. Starting follow-up 1 year after pneumonia to reduce the potential influence of surveillance bias and the risk of reverse causation, the adjusted hazard ratio for CKD in the first 5 years of follow-up was 5.20 (95% confidence interval, 3.91-6.93) and then attenuated with increasing time.

Conclusion: Pneumonia among inpatients is associated with a persistently increased risk for subsequent CKD, with the highest risk during the years immediately after pneumonia. Health care professionals should be aware of this period of heightened risk to facilitate early diagnosis and secondary preventive interventions.

Background: Cystatin C may add explanatory power for associations with mortality in combination with other filtration markers, possibly indicating pathways other than glomerular filtration rate (GFR). However, this has not been firmly established since interpretation of associations independent of measured GFR (mGFR) is limited by potential multicollinearity between markers of GFR. The primary aim of this study was to assess associations between cystatin C and mortality, independent of mGFR. A secondary aim was to evaluate the utility of combining cystatin C and creatinine to predict mortality risk.

Methods: Cox regression was used to assess the associations of cystatin C and creatinine with mortality in 1157 individuals referred for assessment of plasma clearance of iohexol.

Results: Since cystatin C and creatinine are inversely related to mGFR, cystatin C - 1 and creatinine - 1 were used. After adjustment for mGFR, lower cystatin C - 1 (higher cystatin C concentration) and higher creatinine - 1 (lower creatinine concentration) were independently associated with increased mortality. When nested models were compared, avoiding the potential influence of multicollinearity, the independence of the associations was supported. Among models combining the markers of GFR, adjusted for demographic factors and comorbidity, cystatin C - 1 and creatinine - 1 combined explained the largest proportion of variance in associations with mortality risk ( R 2 = 0.61). Addition of mGFR did not improve the model.

Conclusions: Our results suggest that both creatinine and cystatin C have independent associations with mortality not explained entirely by mGFR and that mGFR does not offer a more precise mortality risk assessment than these endogenous filtration markers combined.

Background: Although acute onset kidney complications associated with severe infections including pneumonia are well characterized, little is known about possible subsequent delayed risk of chronic kidney disease (CKD).

Patients and methods: Associations between hospital admission with pneumonia in adulthood and raised risks of subsequent CKD were evaluated in a cohort of all male residents in Sweden born from 1952 to 1956 (n=284,198) who attended mandatory military conscription examinations in late adolescence (n=264,951) and were followed up through 2009. CKD and pneumonia were identified using Swedish national registers, and their associations were evaluated using Cox regression. Excluding the first year, the subsequent period was divided into <= 5, > 5-<= 15, and > 15 years after hospital admission with pneumonia. Follow-up ended on the date of first incident diagnosis of kidney disease, death, emigration, or December 31, 2009, whichever occurred first.

Results: During a median follow-up of 36.7 (interquartile range 35.3-37.9) years from late adolescence, 5,822 men had an inpatient pneumonia diagnosis without contemporaneous kidney disease. Among exposed men, 136 (2.3%) were later diagnosed with CKD compared with 2,749 (1.2%) of the unexposed. The adjusted hazard ratio for CKD in the first year after the first episode of pneumonia was 14.55 (95% confidence interval, 10.41-20.32), identifying early onset kidney complications and possibly pre-existing undiagnosed CKD. Starting follow-up 1 year after pneumonia to reduce the potential influence of surveillance bias and the risk of reverse causation, the adjusted hazard ratio for CKD in the first 5 years of follow-up was 5.20 (95% confidence interval, 3.91-6.93) and then attenuated with increasing time.

Conclusion: Pneumonia among inpatients is associated with a persistently increased risk for subsequent CKD, with the highest risk during the years immediately after pneumonia. Health care professionals should be aware of this period of heightened risk to facilitate early diagnosis and secondary preventive interventions.

Background: Identification of predictors of end-stage renal disease (ESRD) in adolescence could provide intervention targets and improve understanding of the cause.

Study Design: Register-based nested case-control study.

Setting & Participants: A cohort of all Swedish male residents born from 1952 through 1956 who attended mandatory military conscription examinations in late adolescence was used to identify 534 cases and 5,127 controls matched by birth year, county, and vital status.

Measurements: Physical working capacity and cognitive function score in late adolescence. Head of household's occupation and household crowding measured as person-per-room ratio from the 1960 census when participants were children.

Results: Proteinuria is associated notably with future ESRD, with an adjusted OR of 7.72 (95% CI, 3.94-15.14; P < 0.001) for trace or positive dipstick findings. ESR has a dose-dependent association with ESRD with an adjusted OR of 2.07 (95% CI, 1.14-3.75; P = 0.02) for ESR > 15 mm/h. Hypertension is associated strongly with future ESRD with an OR of 3.97 (95% CI, 2.08-7.59; P < 0.001) for grade 2 hypertension and higher. Elevated BMI is associated statistically significantly with increased ESRD risk with an OR of 3.53 (95% CI, 2.04-6.11; P < 0.001) for BMI >= 30 compared with 18.5-<25kg/m(2).

Limitations: The study was limited to men, with no initial estimation of glomerular filtration rate, and information on smoking was unavailable.

Conclusions: ESR, proteinuria, BMI, and blood pressure in late adolescence are independent predictors of ESRD in middle-aged men. This highlights the long natural history and importance of adopting a life-course approach when considering the cause of chronic kidney disease. (C) 2014 by the National Kidney Foundation, Inc.